Schizophrenia has traditionally been thought to be a disease with onset of symptoms during adolescence or early adulthood. Hence very little systematic research has been done on late-onset schizophrenia (LOS), especially in the USA. Over the past 9 years, we have studied rigorously diagnosed 241 middle-aged and elderly outpatients with schizophrenia and 143 normal comparison subjects. The age of onset of schizophrenia has ranged from 12 to 76. Our studies have shown several similarities between LOS and early-onset schizophrenia (EOS) in terms of positive symptoms, family history, course, neuroleptic responsiveness, and nonspecific neuropsychological and MRI abnormalities, suggesting that LOS is indeed a form of schizophrenia with neurodevelopmental origins. On the other hand, we have also found a number of critical differences in gender distribution, subtype characterization, negative symptoms, neuroleptic dose, and specific neuropsychological deficits as well as MRI abnormalities (e.g., larger thalamus). These differences suggest that LOS is likely to be a neurobiologically distinct subtype of schizophrenia. Our data from several different domains support the notion that LOS is best defined as schizophrenia with onset of prodromal symptoms at or after age 40. We believe that we probably have the best-ever characterized sample of LOS patients along with appropriate comparison groups that we have been following longitudinally. We now propose to expand our sample by adding new subjects, as well as important comparison group of patients with late-onset delusional disorder (LODD). The study of LODD will help validate its diagnostic status, and also determine specificity of certain cognitive and MRI characteristics of LOS. Additionally, we will continue to follow the subjects in our current cohort. Some of our assessment methods will be modified so as to make them more sensitive (e.g., MRI quantitative analysis, outcome and functioning measures) to the new questions being asked. Our studies should have a major impact on the understanding of schizophrenia and aging.